An efficient organocatalytic enantioselective synthesis of spironitrocyclopropanes

Article abstract of DOI:10.1039/c2ob26943k

An organocatalytic asymmetric synthesis of spironitrocyclopropanes has been demonstrated starting from 2-arylidene-1,3-indandiones and bromonitroalkanes catalyzed by a cinchona-derived bifunctional organocatalyst. The products were obtained with excellent enantioselectivities, diastereoselectivities and with good yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2ob26943k

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An efficient organocatalytic enantioselective synthesis
of spironitrocyclopropanes†
Cite this: Org. Biomol. Chem., 2013, 11, 44
Received 4th October 2012,
Accepted 22nd October 2012
Utpal Das, Yi-Ling Tsai and Wenwei Lin*
DOI: 10.1039/c2ob26943k
www.rsc.org/obc
An organocatalytic asymmetric synthesis of spironitrocyclopro- successful. As evident in the literature,10a,d cinchona alkaloid
panes has been demonstrated starting from 2-arylidene-1,3- derived thioureas12 are well known for their bifunctional be-
indandiones and bromonitroalkanes catalyzed by a cinchona- havior to activate electron poor alkenes and pronucleophiles
derived bifunctional organocatalyst. The products were obtained simultaneously. Accordingly, we planned to use bifunctional
with excellent enantioselectivities, diastereoselectivities and with catalysts (I–IV) for our study of nitrocyclopropanation.
good yields.
Thiourea catalysts V–VI derived from cyclohexane diamine
were also included for our study. In a continuation of our
recent efforts,13 herein we wish to report our attempts to
prepare enantioenriched spironitrocyclopropane derivatives.14
We began our study by using 1a (alkene component) and bromo-
nitromethane (2a, pronucleophile) as the model reaction
partners in the presence of quinidine derived bifunctional
tertiary amine-thiourea catalyst I. Na2CO3 was used to neutralize
the liberated HBr. However, our initial attempt at the predicted
nitrocyclopropanation was unsuccessful, and only a trace
amount of the expected product was detected (Table 1, entry 1).
We reasoned that this failure was due to a lack of hydrogen-
bond interactions between the N–H bonds of thiourea and the
1,3-dicarbonyl groups of 1a. Water is well known for its ability
to participate in hydrogen bonding interactions and many orga-
nocatalytic reactions are known to proceed in water.15 Unfortu-
nately, we did not observe any conversion of starting material
when the reaction was conducted in water (entry 2). To our sur-
prise, we noted that precise quantities of water were critical for
the reaction to proceed. In the presence of one equivalent of
water the reaction proceeded smoothly to furnish the nitrocyclo-
propanation adduct (3a) in 49% isolated yield in just two hours
with 75% ee at room temperature (entry 3). Lowering of the
reaction temperature to 0 °C was beneficial as product 3a was
obtained in 76% yield with a diasteremeric ratio of 11 : 1 and
91% enantiomeric excess (entry 4).
Several biologically active compounds and natural products are
known to have cyclopropane rings as important structural sub-
units.1 Among them, nitrocyclopropanes are of special interest
because they can be found in various biologically active
natural products.2 Moreover, they serve as the key intermedi-
ates for many useful synthetic transformations.3 As a result,
asymmetric cyclopropanations have been well explored, includ-
ing enantioselective versions of Simmons–Smith reactions4
and transition metal catalyzed reactions using carbene inter-
mediates.5 An alternative path for catalytic cyclopropanation
was introduced by Aggarwal,6 Gaunt7 and MacMillan8 invol-
ving ylides9 as intermediates.
In recent years, organocatalytic asymmetric cyclopropana-
tion reactions were found to be an attractive alternative, and
many elegant strategies were reported.10 However, the direct
organocatalytic synthesis of spirofused nitrocyclopropanes is
very limited10a,d and that employing 2-arylidene-1,3-indan-
diones (1) has not yet been reported. The substrates 1 are
known as a restricted class of trisubstituted electron poor
alkenes and have rarely been used in organocatalysis.11 Very
recently, Lattanzi and co-workers11a described an elegant Michael-
initiated cascade reaction to prepare spirocyclopropanes
starting from 1. However, their attempted base-catalyzed
cyclopropanation of 1 with bromonitromethane (2) was not
Encouraged by this promising output, we also evaluated
other cinchona alkaloid derived catalysts (II–IV) and catalysts
V–VI, and the results are presented in Table 1 (entries 5–9).
Although all the catalysts (I–IV) could promote the reaction,
catalyst I was found to be better in terms of chemical yield and
enantioselectivity. However catalysts V and VI turned to be very
poor, as not only did the reaction take longer (<70% conver-
sion in the indicated time), but also the obtained products
Department of Chemistry, National Taiwan Normal University, 88, Section 4,
Tingchow Road, Taipei 11677, Taiwan, R.O.C. E-mail: wenweilin@ntnu.edu.tw;
Fax: (+886) 229324249; Tel: (+886) 277346131
†Electronic supplementary information (ESI) available: Experimental procedure,
spectral data of new compounds. CCDC 892806 (3a) and 892808 (3k). For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26943k
44 | Org. Biomol. Chem., 2013, 11, 44–47
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Table 1 Optimization of enantioselective nitrocyclopropanation reaction
between 1a and 2aa
Table 2 Substrate scope for the enantioselective spironitrocyclopropanationa
Entry
R1
R2
t (h)
3,b (%)
drc
eed (%)
1
4-BrC6H4
4-ClC6H4
4-NO2C6H4
4-CNC6H4
2-BrC6H4
3-FC6H4
H
6
8
3a, 79
3b, 68
3c, 68
3d, 78
3e, 68
3f, 71
3g, 78
3h, 68
3i, 65
3j, 63
3k, 81
3l, 88
3m, 78
3n, 65
—
19 : 1
19 : 1
18 : 1
19 : 1
19 : 1
16 : 1
18 : 1
18 : 1
18 : 1
18 : 1
19 : 1
19 : 1
19 : 1
16 : 1
—
96 (>99)
95
2
H
3
H
8
86
4
H
12
8
7
10
5
5
6
92
5
H
96 (>99)
86
6
H
7
C6H5
H
96
8
4-MeC6H4
2-MeC6H4
4-tBuC6H4
4-BrC6H4
C6H5
4-MeC6H4
4-BrC6H4
Cyclohexyl
4-OMeC6H4
H
96
9
H
96
10
11
12
13
14
15e
16
H
98
Me
Me
Me
Et
H
12
24
36
72
8
96 (>99)
93
96
Entry
Cat.
Solvent
t (h)
3ab (%)
drc
eed (%)
56
—
1e,f
2e
3e
4
I
Toluene
H2O
24
24
2
—
—
49
76
69
65
79
49
49
78
64
49
79
79
—
—
—
—
75
91
−91
−88
−75
H
24
—
—
—
I
a Reaction conditions: 1a–l (0.1 mmol), 2a–c (1.5 equiv.),
I (20 mol%), Na2CO3 (1 equiv.) in 0.2 mL anhydrous toluene.
I
I
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
6.5 : 1
11 : 1
11 : 1
10 : 1
12 : 1
—
5
1
b Isolated yield. c Determined by H NMR spectroscopic analysis of
5
II
III
IV
V
VI
I
5
the crude reaction mixture. d ee for the major isomer (ee after
single recrystallization). e A mixture of three compounds (70% ee,
87% ee and 72% ee) were obtained (please also see ESI†).
6
5
7
6
8
48
30
6
9
—
10
11
12g
13h
14h,i
6.5 : 1
4.3 : 1
11 : 1
19 : 1
16 : 1
87
67
90
94
88
I
6
I
Toluene
Toluene
Toluene
48
6
scope and generality of the methodology were examined.
A variety of substituents on 2-arylidene-1,3-indandiones (1a–l)
and different bromonitroalkanes (2a–c) could be employed to
provide spironitrocyclopropanes (3a–n) in good yields (up to
88%), excellent diastereoselectivities (up to 19 : 1) and enantio-
selectivities (up to 98%) (Table 2). The electronic nature, bulki-
ness or positions of substituents in the aryl group seems to
have little effect on the results (entries 1–10). Slightly reduced
enantioselectivities were observed in the cases of 4-nitrophenyl
and 3-fluorophenyl substituted arylidene-1,3-indandiones
(1c and 1f). We have also evaluated substituted bromonitro-
alkanes (2b and 2c) as pronucleophile (entries 11–14) for syn-
thesis of the products 3k–n bearing a quaternary stereocenter,
which is considered a challenging task in organic synthesis.16
Thus the reaction of 1-bromo-1-nitroethane (2b) with substi-
tuted 2-arylidene-1,3-indandiones having different electronic
natures proceeded smoothly to give the desired products
(3k–m) in good yields, excellent diastereoselectivities and
enantioselectivities (entries 11–13). It is noteworthy that the
reaction between 1-bromo-1-nitropropane (2c) and 1a was
slower and the product (3n) was obtained in moderate enantio-
selectivity (56%) albeit with good yield and diastereoselec-
I
I
14
a Reaction conditions: 1a (0.1 mmol), 2a (1.5 equiv.), cat.
(20 mol%), base (1 equiv.) in 0.5 mL anhydrous solvent. b Isolated
yield. c Diastereomeric ratio was determined by 1H NMR
spectroscopic analysis of the crude reaction mixture.
d Enantiomeric excess was determined by HPLC analysis. e At
room temperature. f No water was used as an additive. g NaHCO3
was used. h The reaction was performed at −20 °C in 0.2 mL
toluene. i 10 mol% I was used.
were racemic. The organocatalytic nitrocyclopropanation reac-
tion for the formation of 3a was then further optimized. A
number of different solvents and bases were screened (entries
10–13, for details see ESI†), and the results indicate that
proper choice of solvent and base play an important role.
Adduct 3a was afforded in reduced diastereoselectivity and
enantioselectivity when the reaction was conducted in dichloro-
methane or tetrahydrofuran (entries 10 and 11). Product 3a
could be formed with a similar product profile (entry 12) using
the weaker sodium bicarbonate base, but the progress of reac-
tion was too slow. When the reaction temperature was further
lowered to −20 °C, 3a was furnished in 94% ee coupled with
19 : 1 diastereoselectivity and 79% yield (entry 13). It is worth
mentioning that both the diastereoselectivity and enantioselec-
tivity of 3a dropped upon lowering of catalyst loading (10 mol%)
under these reaction conditions (entry 14).
tivity (entry 14 vs.
1 and 11). Less reactive cyclohexyl
substituted alkylidene-1,3-indandiones were also examined
with 2a. However, a poor result was obtained under our reac-
tion conditions (entry 15).17 Additionally, cyclopropanation of
4-methoxyphenyl substituted arylidene-1,3-indandione (1l)
and 2a did not take place under identical reaction conditions
With an effective protocol for the enantioselective
formation of spironitrocyclopropane in hand, the substrate
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determined by single crystal X-ray data analyses and those of
the others were assigned by analogy.19
We believe that the reaction proceeds through simultaneous
activation of the pronucleophile (bromonitroalkane) and
electrophilic 2-arylidene-1,3-indandiones via water assisted
H-bonding interaction by the bifunctional catalyst. Nucleo-
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products (see ref. 10d).
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(3g) can also be accessed by employing bromonitrostyrene,
such as 4, as a dielectrophilic component10a,20 and 1,3-indan-
dione (5) as a dinucleophile in presence of appropriate cata-
lyst. However, our initial attempt to use the present optimized
reaction conditions was not very successful and the adduct
ent-3g was obtained with only 35% ee and moderate yield
(57%) (Scheme 1).
In summary, we have developed an efficient asymmetric
pathway for the preparation of spironitrocyclopropanes cata-
lyzed by cinchona-derived bifunctional organocatalysts. To the
best of our knowledge, this is the first asymmetric route to
prepare spironitrocyclopropanes starting from 2-arylidene-1,3-
indandiones and bromonitroalkanes. The products were
obtained in good yields (up to 88%), excellent enantioselec-
tivities (up to 98%) and diastereoselectivities (up to 19 : 1).
Further investigation of the synthetic route described in
Scheme 1, biological evaluation of spironitrocyclopropanes
and investigation of the reaction mechanism are currently
underway in our laboratory.
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Acknowledgements
The authors thank the National Science Council of the Repub-
lic of China (NSC 99-2119-M-003-004-MY2) and National
Taiwan Normal University (NTNU100-D-06) for financial
support.
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